[Radiotherapy and combined modality treatment of advanced gastrointestinal tumors. Analysis of morbidity in 101 patients]. / Strahlentherapie und kombinierte Behandlung fortgeschrittener gastrointestinaler Tumoren. Eine Morbiditätsanalyse an 101 Patienten.

Despite numerous reports about combined therapy of gastrointestinal tumours no detailed analysis of considerably manifold side effect has been established. In this study the therapeutic results and morbidity of irradiation in 64 patients are compared with 37 courses of combined therapy for recurrences and/or metastases. Modalities in combined therapy consisted of radiotherapy and hyperthermia or chemotherapy, or chemotherapy and hyperthermia respectively. Toxicity from combined therapy was seen more frequently and pronounced, requiring variations in therapy management up to 54% versus 17% in patients irradiated. Dose reductions (15% vs. 8%), intervals (30% vs. 14%) and its duration (14 vs. 6 days) extended the overall treatment times. In 21% combined therapy was interrupted totally (vs. 11% mainly caused by non therapy specific other diseases, respectively rapid tumour progression) or in another 13% continued sequentially. No improved results were seen following combined therapy, but an intolerably high risk of serious complications (up to 71% in combination of radio- and chemotherapy). With the dosages, fractionations and techniques used combined therapy can be performed only in a sequential course for palliation of advanced gastrointestinal tumours. We assume that morbidity of hyperthermia in most cases is considerably higher than its therapeutic gain.

[Simultaneous cisplatin and radiotherapy of locally advanced squamous cell carcinomas of the head and neck region. A clinical pilot study]. / Simultane Cisplatin- und Bestrahlungstherapie lokal fortgeschrittener Plattenepithelkarzinome der Kopf-Hals-Region. Eine klinische Pilotstudie.

Cisplatin (20 mg/m2 on five successive days, together with hydration and osmotic diuresis) was administered in two treatment cycles to 32 patients with locally advanced tumours (T2-4, N1-3, M0) of the head and neck region. Cisplatin-free interval was at least four weeks. At the same time there was radiotherapy with photons or electrons, daily fractions of 2 Gy four to five times weekly to a final volume dose of 60-70 Gy. Tumour resection was undertaken if there was no tumour involution of at least 50% after 40 Gy and one cisplatin cycle. Total remission rate (complete and partial) was 91%. Complete remission occurred in 22 patients (69%). Biopsies in 14 patients after 40 Gy and one cisplatin cycle indicated that in seven there was no histological evidence of tumour. There was no clinically serious rise in local toxicity. However, erythema and oedema in the radiation fields were more frequent and earlier than with radiotherapy alone. The results indicate that combined cisplatin administration and radiotherapy give the same or even better results than aggressive chemotherapy followed by radiotherapy.

[A new interdisciplinary treatment concept for head and neck tumors. Fundamentals, practicability and initial clinical results]. / Ein neues interdisziplinäres Behandlungskonzept bei fortgeschrittenen Kopf-Hals-Tumoren. Grundlagen, Praktikabilität und erste klinische Ergebnisse.

Surgery and subsequent irradiation are still considered as the basic treatment of advanced head and neck tumours. Improvements may be achieved by initial combined chemotherapy. However, this regimen has not yet been statistically substantiated. In order to reduce the therapeutic morbidity, Cis-platinum was given as a cytotoxic and radiosensitizing agent simultaneously with percutaneous irradiation. In case of partial tumour regression after a target volume dose of 40 Gy, radiotherapy was continued up to 60 or 70 Gy respectively. In case of minor tumour response, surgery was interposed after a dose of 40 Gy, followed by completing radiotherapy. After a maximum follow-up period of 14 months, 18 out of 22 patients show no evidence of tumour. In two cases a partial regression is seen. One patient died from intercurrent disease, another from uncontrolled primary. This tumour control rate is comparable to the data achieved with initial combined chemotherapy regimens, at a lower level of morbidity. Our preliminary results seem to corroborate the experimentally proven enhancement effect of Cis-platinum.

Present interdisciplinary treatment regimen for advanced head and neck tumours at the West German Tumour Centre, Essen.

Apart from the classic combination of surgery and irradiation, four other treatment modalities are presently being evaluated in advanced head and neck tumours. These are: 1) antineoplastic chemotherapy 2) radiosensitizing agents 3) high LET radiotherapy 4)local hyperthermia Preoperative chemotherapy, followed by surgery and irradiation, has improved the local control as well as survival rates in phase II trials. Cis-platinum may yield some additional benefit due to its radiosensitizing properties. Radiosensitizing drugs such as nitro-imidazoles have so far failed to show any advantage in randomized trials, since neurotoxicity prevented maximum effective concentrations. The same is true for high LET radiotherapy with neutrons as compared to conventional irradiation. Local hyperthermia is considered as a palliation at the present time, when all other treatment modalities have been exhausted. In our centre, the preliminary results of radiotherapy and sensitization with cis-platinum in combination with surgery are encouraging. Some methods are discussed which permit the prediction of prognostic criteria for tumors under treatment. This may contribute to the optimization of individual treatment regimes in the future.

[Analysis of morbidity from simultaneous 5-fluorouracil therapy and radiation therapy in advanced gastrointestinal tumors. Report of results]. / Morbiditätsanalyse der gleichzeitigen 5-Fluorouracil- und Strahlentherapie bei fortgeschrittenen gastrointestinalen Tumoren. Ein Erfahrungsbericht.

Simultaneous application of 5-fluorouracil and radiotherapy is generally accepted in the treatment of gastrointestinal tumours. However, in 10 patients with metastatic gastrointestinal tumours we observed intolerable toxicity during this combined treatment regimen. Because of gastrointestinal and haematological toxicity the combined modality was interrupted in all patients. Given sequentially, this regimen was tolerated. Our experience indicates that an intolerable high rate of toxicity has to be taken into consideration in case of the simultaneous combination of 5-fluorouracil and radiotherapy.

Pharmacokinetics of ticarcillin during cisplatin chemotherapy.

Cancer chemotherapeutic agents and antimicrobial antibiotics are often given concomitantly. Cisplatin, which has become increasingly important in cancer treatment, has shown nephrotoxicity as a dose-limiting feature. The alpha-carboxy-penicillin ticarcillin (tc) has a wide spectrum of antimicrobial activity, especially against Pseudomonas. The plasma half-life of tc is correlated with renal function. The combined use of cisplatin (20 mg/m2, days 1-5) and tc (3 X 5 g/24 h, days 1-5) with renal protection by vigorous hydration (2400 ml of 0.9% NaCl/24 h continuous infusion, days 1-5) in a group of 12 cancer patients did not alter the BUN and creatinine serum levels. The mean serum concentration of tc, which was monitored in a patient 15, 30, and 45 min after injection of 5 g on 4 consecutive days together with cisplatin, did not differ from the levels of tc reported when used without concomitant cisplatin therapy. Thus these preliminary data show that the pharmacology of tc may not be altered significantly when applied together with cisplatin and that cumulative nephrotoxicity must not be expected with this combination when sufficient hydration is used.

[Cisplatin as a radiosensitizer in the treatment of solid tumours--a clinical pilot study]. / Cisplatin als radiosensibilisierende Substanz bei der Behandlung solider Tumoren.

A variety of experimental tumour models have shown that cisplatin in combination with ionizing radiation enhances tumour regression. To evaluate the feasibility, efficacy and toxicity of a combined regimen, 25 patients with different solid tumours were treated with cisplatin and photon irradiation. A local tumour control was achieved in 22 cases. Thirteen patients with squamous cell carcinoma of the lung (T1-3, N1-2, M0) received cisplatin (20 mg/m2 per day) on 5 consecutive days with NaCl hyperhydratation (0,9% NaCl, 2400 ml/24 hours as continuous infusion) in the first and last week of radiotherapy (5 X 2 Gy/week, 56 Gy target volume dose). 12 of 13 patients have shown local tumour control. Increased clinically evident side effects were not observed. From the underlying data the conclusion is drawn that the experimental results are reproducable under clinical conditions and that improved local tumour response rates can be achieved.

[Individualized interval shortening in the chemotherapeutic induction treatment of solid tumors (author's transl)]. / Individualisierte Intervallverkürzung bei der chemotherapuetischen Induktionsbehandlung solider Tumoren.

Sequential chemotherapy with vinblastin and bleomycin, as well as adriamycin and cis-platin, was administered to 29 patients with disseminated malignant testicular teratoma. In order to intensify the induction phase, the intervals between drug administrations were individually shortened, with the next course of treatment following directly after the phase of critical leucocyte depression. This method was pursued over four courses of chemotherapy without dose reduction, followed by courses of chemotherapy in a conventional three-weekly rhythm. A response was obtained in 28 patients, 18 of them achieving complete remission. Taking into consideration unfavourable prognostic factors in the treatment group, this result is better than after the same chemotherapy at three-weekly intervals. Induction treatment adapted to leucocyte response carries with it the risk of higher toxicity, but this would seem to be acceptable in view of the improved long-term prognosis. This or similar intensification of the first treatment phase, for a long time used with leukaemias, could also be considered in the management of various chemotherapy-sensitive solid tumours, especially in younger patients.

[Chemotherapy in advanced sarcomas (author's transl)]. / Chemotherapeutische Behandlungsmöglichkeiten bei fortgeschrittenen Sarkomen.

43 patients with metastasizing sarcomas were treated with a combination of either vincristin, adriamycin and cis-platinum (n = 21) or ifosfamide and cis-platinum at three weeks' intervals in each case. Ten patients responded to the first combination and nine to the second combination with objective tumor regression. Particularly the latter result is remarkable since 16 of the 22 patients had already been pretreated with combinations containing adriamycin. Obviously the combination of ifosfamide and cis-platinum is a promising alternative in metastasizing sarcomas of the bones and soft tissue, especially if the CYVADIC combination--which is often regarded as standard treatment--remained unsuccessful. This has no bearing on additional surgical measures or on radiotherapy which may be necessary in some patients.

[Radiotherapy in case of intracerebral formation of metastases of non-seminomatous testicle tumors (author's transl)]. / Strahlentherapie bei intrazerebraler Metastasierung nichtseminomatöser Hodentumoren.

The subject of this study were non-seminomatous testicle tumors with cerebral formation of metastases. Despite the relatively low radiosensitivity of the primary tumors and their regional metastases eighteen of twenty patients were free of symptoms, and a complete regression of the intracerebral tumors was shown by computed tomography and/or scintigraphy in ten of twenty cases. This regression was obtained within two or three weeks by an irradiation of the skull with a focal dose of 30 to 40 Gy. Due to the small number of patients (20), it was not possible to demonstrate a statistically different receptiveness of the cerebral metastases according to their histological subentity. Because of the subjective stress, the duration of radiotherapy should be as short as possible (e.g. 30 Gy in 10 fractions over a period of two weeks). In our opinion, irradiation is clearly indicated in case of testicle teratomas with cerebral formation of metastases. Practically the only contra-indications are a strong intracranial hypertension as well as hyperkinesia. The entire prognosis of the patient, however, is not determined by the cerebral formation of metastases but by the pulmonary metastatic extension, so that radiotherapy is an important palliative factor with regard to the survival time of these patients.

[Brain metastases in malignant testicular teratomas]. / Hirnmetastasen bei malignen Hodenteratomen.

Between 1974 and 1979 a total of 344 patients with testicular teratomas were treated at the West German Tumor Center, Essen. Brain metastases were encountered in 16 patients by means of neurologic symptoms as well as scintigraphy and computerized tomography. Cerebral involvement was closely related to preexistent lung metastases (n = 162) and the risk appeared to increase with the duration of pulmonal disease amounting to about 10% (16/162) in this group. Radiotherapy was the treatment of choice and produced objective and subjective improvement in 13 of 16 cases. Thus, long-term prognosis of patients with brain metastases was mainly determined by the preexistent metastatic involvement of the lungs.

Autonomous cortisol secretion by a metastatic Leydig cell carcinoma associated with Klinefelter's syndrome.

We present the case of a 39-year-old man with Klinefelter's syndrome and a metastatic Leydig cell carcinoma in whom autonomous cortisol production induced by the interstitial cell tumor was found. Apart from the Cushing's syndrome the endocrine activity of the tumor was demonstrated by the secretion of estradiol, estrone, alkaline phosphatase, and testosterone. This is, to our knowledge, the first description of a Cushing's syndrome not caused via ACTH production but directly induced by ectopic steroid production. While being resistent to chemotherapy and radiation, the tumor responded favorably to treatment with o,p'-DDD. The reduction of tumor size was accompanied by a continuous decrease of serum markers. The etiology of the tumor is discussed in the light of the hormonal derangement caused by the genetic abnormality of Klinefelter's syndrome.

[Sequential combination chemotherapy with vinblastine/bleomycin and adriamycin/cis-dichlorodiammineplatinum (II) in non-seminomatous testicular cancer. I. Results of a prospective randomized phase III-study with 71 patients with disseminated disease (stage IV) (author's transl)]. / Sequentiell alternierende Chemotherapie nicht-seminomatöser Hodentumoren mit Velbe/Bleomycin und Adriamycin/Cisplatin. I. Ergebnisse einer randomisierten Studie bei 71 Patienten mit pulmonaler Metastasierung (Stadium IV).

74 patients with disseminated non-seminomatous testicular cancer were randomly entered on a prospective sequential combination chemotherapy regimen with mandatory crossover, consisting of either vinblastine/bleomycin or adriamycin/cis-dichlorodiammineplatinum (II) (DDP) as initial therapy. Independent of the randomization the overall remission rate in 71 evaluable patients was 89% including 54% complete remissions. 35% of the patients remained disease-free at 2+ to 28+ months with a median of 12 months. By additional surgical removal of residual pulmonary metastases in two patients the complete remission rate was increased to 40/71 (56%), and the number of patients with no evidence of disease to 27/71 (38%). According to the life-table method the two-years survival rates were 63% for complete responders and 29% for all other patients, which was significantly lower. 53 patients (75%) were alive at 3 to 28 months with a median of 9 months. Additional advanced abdominal disease, initially elevated beta-HCG and LDH and extension of pulmonary disease were of significant negative influence on the prognosis. The evaluation of single chemotherapy courses revealed equal efficacy of both combinations. However, response to adriamycin/DDP occurred in 46% of the courses, when vinblastine/bleomycin had failed, while response to vinblastine/bleomycin occurred only in 21% of the courses when adriamycin/DDP had failed. Thus different patterns of cross-resistance between these alternative regimens may exist.

[Improved antiemetic treatment with levomepromazine (author's transl)]. / Verbesserte antiemetische Behandlung mit Levomepromazin bei zytostatikabedingtem Erbrechen.

The antiemetic effect of levomepromazine (Neurocil) was tested in 76 patients treated for metastasizing malignancies with cis-dichlorodiammineplatinum (II) (Platinex). In all patients conventional antiemetics had been ineffective against gastrointestinal side effects of platinum. Using levomepromazine vomiting and nausea could be successfully prevented in 47 out of 63 patients on conventional cis-platinum doses (20 mg/m2 for 5 consecutive days) and in 5 out of 13 patients on high single day dosages (100 mg/m2). In most other patients clear-cut subjective improvement occurred. The antiemetic effect of levomepromazine against cis-platinum, which ranks among the most widely used cytostatics and causes gastrointestinal symptoms, is of importance in medico-oncological practice as it causes relief for the patients.